EP0049638B1 - Process for prepararing 5-methyl-4-imidazolecarboxylic acid esters - Google Patents

Process for prepararing 5-methyl-4-imidazolecarboxylic acid esters Download PDF

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Publication number
EP0049638B1
EP0049638B1 EP81304640A EP81304640A EP0049638B1 EP 0049638 B1 EP0049638 B1 EP 0049638B1 EP 81304640 A EP81304640 A EP 81304640A EP 81304640 A EP81304640 A EP 81304640A EP 0049638 B1 EP0049638 B1 EP 0049638B1
Authority
EP
European Patent Office
Prior art keywords
acid
methyl
formaldehyde
added
ethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
EP81304640A
Other languages
German (de)
English (en)
French (fr)
Other versions
EP0049638A1 (en
Inventor
Harold Graboyes
Thomas James Kasper
Praful Dalichand Vaidya
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Priority to AT81304640T priority Critical patent/ATE26265T1/de
Publication of EP0049638A1 publication Critical patent/EP0049638A1/en
Application granted granted Critical
Publication of EP0049638B1 publication Critical patent/EP0049638B1/en
Expired legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • This invention relates to a process for preparing 5-methyl-4-imidazolecarboxylic acid esters from acetoacetic acid esters.
  • the 5-methyl-4-imidazolecarboxylic acid esters which are the products of this process are useful as intermediates for preparing histamine H 2 -antagonists, for example cimetidine.
  • Cimetidine which is N-cyano-N'-methyl-N"-[2-(5-methyl-4-imidazolylmethylthio)ethyl]guanidine, is a histamine H 2 -receptor blocking agent of value as an inhibitor of gastric acid secretion. Cimetidine is widely used in the treatment of duodenal ulcers.
  • Durant et al. in U.S. 3,950,333, described the preparation of 4-substituted-5-imidazolecarboxylic acid ethyl esters by reaction of an ethyl alkanoylacetate with sodium nitrite, reduction of the resulting ethyl 2-hydroxyimino-3-oxoalkanoate to give the 2-amino-3-oxo compounds and treatment of that compound with formamide.
  • 5-methyl-4-imidazolecarboxylic acid esters are prepared by the following procedure: in which R is lower alkyl having 1-4 carbon atoms or benzyl.
  • the process of this invention is carried out without isolating the two intermediates, i.e. (2) and (3) above.
  • the preferred process may be represented as follows:
  • a lower alkyl ester of acetoacetic acid is reacted with nitrous acid.
  • the nitrous acid is preferably generated by reacting sodium nitrite with an acid, preferably acetic acid. This reaction is preferably carried out at reduced temperature, for example at 0-15°C, for about 3-6 hours. If isolation of the hydroxyimino intermediate (2) is desired, ethyl acetate is the preferred solvent.
  • the resulting mixture containing the diketo compound, i.e. a,(3-dioxobutyric acid ester, and formaldehyde is treated with aqueous ammonia to raise the pH to 3 to 5.
  • the reaction mixture is held at 65-70°C for about 30-60 minutes, then ammonia is added to neutralize the reaction mixture (pH 7). Cooling and filtering gives the 5-methyl-4-imidazolecarboxylic acid ester.
  • the 5-methyl-4-imidazolecarboxylic acid esters prepared by the process of this invention may be used to prepare histamine H 2 -antagonists, in particular cimetidine, by reducing the ester to give the 5-methyl-4-hydroxymethylimidazole, reacting the hydroxymethyl compound with cysteamine and then reacting the resulting 5-methyl-4-[(2-aminoethyl)thiomethyl]imidazole with dimethyl-N-cyanoimidodithiocarbonate and reacting the resulting N-cyano-N'-[2-((5-methyl-4-imidazolyllmethylthio)ethyl]-S-methylisothiourea with methylamine.
  • These processes are described in U.S. 3,950,333.
  • a process for reducing the ester to the hydroxymethyl compound using alkali metal or calcium in liquid ammonia is described in U.S. 4,063,023.
  • the invention is illustrated by the following examples.
  • the temperatures indicated therein are °C.
  • ethyl 2-hydroxyimino-acetoacetate prepared from 130 g (1 m) of ethyl acetoacetate, was added over 75 minutes to a stirred suspension of 166 ml (3 m) of concentrated sulfuric acid and 105 g (3.5 5 m) of paraformaldehyde at 5-10°. The mixture was stirred at 5-10- for four hours and aqueous ammonia (28%) was added to pH 5 and the temperature rose to 70°. The reaction mixture was held for 30 minutes at pH 5 at 65-70° and then neutralized with aqueous ammonia (28%). The mixture was cooled to 10°. The solid material was filtered off, washed with water and isopropanol and dried to give ethyl 5-methyl-4-imidazolecarboxylate (yield 50%).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
  • Macromonomer-Based Addition Polymer (AREA)
  • Cephalosporin Compounds (AREA)
EP81304640A 1980-10-08 1981-10-07 Process for prepararing 5-methyl-4-imidazolecarboxylic acid esters Expired EP0049638B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT81304640T ATE26265T1 (de) 1980-10-08 1981-10-07 Verfahren zur herstellung von 5-methyl-4imidazolcarbons|ureestern.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US06/195,278 US4328349A (en) 1980-10-08 1980-10-08 Process for preparing 5-methyl-4-imidazolecarboxylic acid esters
US195278 1980-10-08

Publications (2)

Publication Number Publication Date
EP0049638A1 EP0049638A1 (en) 1982-04-14
EP0049638B1 true EP0049638B1 (en) 1987-04-01

Family

ID=22720775

Family Applications (1)

Application Number Title Priority Date Filing Date
EP81304640A Expired EP0049638B1 (en) 1980-10-08 1981-10-07 Process for prepararing 5-methyl-4-imidazolecarboxylic acid esters

Country Status (10)

Country Link
US (1) US4328349A (enrdf_load_stackoverflow)
EP (1) EP0049638B1 (enrdf_load_stackoverflow)
JP (1) JPS5793964A (enrdf_load_stackoverflow)
KR (1) KR880001316B1 (enrdf_load_stackoverflow)
AT (1) ATE26265T1 (enrdf_load_stackoverflow)
DE (1) DE3176061D1 (enrdf_load_stackoverflow)
DK (1) DK399681A (enrdf_load_stackoverflow)
GR (1) GR75373B (enrdf_load_stackoverflow)
IE (1) IE52370B1 (enrdf_load_stackoverflow)
YU (1) YU241781A (enrdf_load_stackoverflow)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4499283A (en) * 1982-06-28 1985-02-12 American Cyanamid Company Process for preparing 1-substituted-6-n-propyl-8-methylimidazo[1,5-d]-as-triazin-4-(3H)-ones
US5138069A (en) * 1986-07-11 1992-08-11 E. I. Du Pont De Nemours And Company Angiotensin II receptor blocking imidazoles
US4880804A (en) * 1988-01-07 1989-11-14 E. I. Du Pont De Nemours And Company Angiotensin II receptor blocking benzimidazoles
US5210079A (en) * 1988-01-07 1993-05-11 E. I. Du Pont De Nemours And Company Treatment of chronic renal failure with imidazole angiotensin-II receptor antagonists
US5354867A (en) * 1988-12-06 1994-10-11 E. I. Du Pont De Nemours And Company Angiotensin II receptor blocking imidazoles
FI916130A0 (fi) * 1989-06-30 1991-12-27 Du Pont Arylsubstituerade imidazoler.
WO1991009022A1 (en) * 1989-12-12 1991-06-27 Novosibirsky Institut Organicheskoi Khimii Sibirskogo Otdelenia Akademii Nauk Sssr 2,2-dialkyl-2h-imidazole-1-oxides and method of obtaining them
WO1991011439A1 (en) * 1990-01-24 1991-08-08 Novosibirsky Institut Organicheskoi Khimii Sibirskogo Otdelenia Akademii Nauk Sssr Derivatives of 4-amino-3-imidazoline-1-oxyl and method of preparation

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1341375A (en) * 1969-11-19 1973-12-19 Smith Kline French Lab Aminoalkylimidazoles and process for their production
US3715365A (en) * 1971-02-08 1973-02-06 Jefferson Chem Co Inc Imidazole synthesis
GB1338169A (en) * 1971-03-09 1973-11-21 Smith Kline French Lab Ureas thioureas and guanidines
GB1401284A (en) * 1971-11-13 1975-07-16 Beecham Group Ltd Imidazole insecticides
US4134983A (en) * 1975-03-03 1979-01-16 Merck & Co., Inc. 3-amino-2-or-propoxyaryl substituted imidazoles
DE2558517C2 (de) * 1975-12-24 1983-11-03 Basf Ag, 6700 Ludwigshafen Verfahren zur Herstellung von 4-Methyl-imidazol-5-carbonsäureisopropylester

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
I.L. Fiman "Organic Chemistry", vol. 1, 6th edition, Longman 1973, p. 302 and p. 177-179 *

Also Published As

Publication number Publication date
IE52370B1 (en) 1987-09-30
ATE26265T1 (de) 1987-04-15
US4328349A (en) 1982-05-04
DK399681A (da) 1982-04-09
DE3176061D1 (de) 1987-05-07
KR880001316B1 (ko) 1988-07-23
YU241781A (en) 1984-02-29
JPS5793964A (en) 1982-06-11
EP0049638A1 (en) 1982-04-14
GR75373B (enrdf_load_stackoverflow) 1984-07-13
IE812346L (en) 1982-04-08
KR830007574A (ko) 1983-11-04

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